Abeta is generated through beta- and gamma-secretase cleavage of amyloid precursor protein (APP). Familial AD has been linked to mutations in APP and one of the components of gammasecretase, implicating Abeta generation in the pathogenesis of AD. Although APP is clearly implicated in AD progression, the normal function and regulation of cleavage of APP is not fully understood. One difficulty in studying APP function has been that APP is partially redundant with two other family members, amyloid precursor-like proteins 1 and 2 (APLP1, APLP2), and combined mutations result in an early postnatal lethality. The first aim of this proposal is to elucidate the relative contributions of APP family members in neuronal differentiation through culturing developing neurons from mice with genetic deletions in APP family members. The roles of full length APP family members and their proteolytic derivatives will be investigated through lentiviral misexpression of these proteins in wild type and mutant neurons. The second aim investigates the function and mechanism of APP action in cortical cell migration by using siRNA constructs to knock down APP in embryonic cortical cells in vivo. The third aim addresses the hypothesis that integrins modulate the function of APP by examining the physical and functional interactions between these protein families. Through these aims the function and mechanism of action of APP family members in developing neurons will be addressed.